The potent anti-obesity effects of serotonin 2C receptors (5-HT2CRs) were first demonstrated through the actions of the diet drug d-Fenfluramine (d-Fen, used in combination as Fen/Phen). While an effective anorexigenic agent, d-Fen also caused valvular heart disease and pulmonary hypertension, likely due to off- target effects. These unexpected side effects highlight the complexity of the central serotonin system. Recently, there has been renewed interest in the serotonin system due to the FDA approval of the new weight- loss drug, Lorcaserin (Belviq), which targets the 5-HT2CRs. However, it is still unclear which specific neuronal populations of the widely expressed 5-HT2CRs directly mediate the anti-obesity effects. In the previous grant period, we focused on defining the neurocircuitry involved in 5-HT2CRs signalling by reactivating 5-HT2CR expression in select neurons. Our findings suggest that the serotonin pathway is highly complex and that 5-HT2CRs have neuroanatomically and functionally distinct roles. While the roles of 5-HT2CRs in arcuate POMC neurons were extensively tested in the previous funding period, the current proposal will focus on functions of 5-HT2CRs in the brainstem (DMV/NTS) and in the paraventricular nucleus (PVH). We hypothesize that 5-HT and 5-HT drugs (including Lorcaserin) are able to act upon distinct populations of 5- HT2CR-expressing neurons to exert different but coordinated effects on energy and glucose homeostasis. In particular, 5-HT2CRs expressed by ARH POMC neurons mediate 5-HT's actions to suppress food intake and prevent body weight gain; 5-HT2CRs in PVH neurons, on the other hand, counteract these anorexigenic effects to promote feeding. In parallel, 5-HT acts via 5-HT2CRs in brainstem NTS/DMV neurons to enhance hepatic insulin sensitivity without influencing food intake and body weight. These questions are especially topical because in addition to Lorcaserin, other 5-HT2CR agonists are also being tested in humans to treat obesity, further reinforcing a need for mechanistic insights on how these compounds exert their effects.